Histologic examination of choroidal neovascular membranes (CNVM) from patients with AMD has demonstrated an abundance of the angiogenic protein, VEGF, and macrophages. Thus, it has been hypothesized that CNVM may result from overexpression of VEGF in the RPE in the setting of a generalized abnormal subretinal wound healing response. To test this hypothesis, an E1-deleted adenoviral vector expressing VEGF (Ad.VEGF) was generated and used to transfect rat RPE cells in-vivo. Findings from this work included the demonstration of VEGF overexpression exclusively from the RPE and the development of CNVM with a morphology akin to that seen in patients with neovascular AMD. This angiogenesis occurred in most eyes 2 weeks after subretinal injection of Ad.VEGF. Interestingly, the development of CNVM was only seen after infection of the RPE at doses of Ad.VEGF that resulted in minimally elevated levels of secreted VEGF. Examination of the CNVM's revealed a choroidal source of the neovascularization with disruption of Bruch's membrane and an invasion of subRPE endothelial cells and pericytes. One novel finding was the maintenance of CNVM at 3 and 4 weeks after Ad.VEGF infection, time points when there is a drop in production of VEGF. This raises the possibility that VEGF may be important in the induction of CNVM but not be critical in the maintenance of these lesions. Histologic examinations of the injected animals have also demonstrated the recruitment of circulating monocytes into the neovascular complex.